The inability of chromosomes to separate properly during meiosis is referred to as non-disjunction (NDJ). NDJ of human chromosome 21 (chr21) is a key event that leads to trisomy 21, also known as Down Syndrome (DS). DS occurs 1 in every 1000 live births and is the leading cause of mental retardation. The goal of the work presented in this proposal is to identify mechanisms of NDJ that occur during oogenesis. More specifically, we will focus on two known risk factors of NDJ, namely advanced maternal age and altered recombination. We will characterize the recombination patterns along nondisjoined chr21 among young, middle and older "oocytes". We will do this for a specific type of NDJ error that is initiated during the first stage of meiosis and continues into the second stage (so-called MM errors). Next, we will characterize recombination breakpoints that most often occur among MM errors (ie. pericentromeric recombinants), to determine the cause for their susceptibility. To accomplish these aims, we will use chr21 genotyping data from families with DS to determine the origin of the nondisjoining error and chr21 recombination profile. We will use a modified tetrad analysis to infer the exchange pattern from the observed recombination data. [unreadable] [unreadable] [unreadable]